Faculty Bibliography

OBJECTIVE:Cortisol excess in Cushing's disease (CD) induces widespread plasma protein alterations, affecting various pathways including coagulation and lipid metabolism. The extent to which these abnormalities normalize during long-term remission remains unclear. DESIGN/METHODS:Cohort study investigating plasma protein profiles in CD patients before, and during long-term remission. METHODS:EDTA plasma samples of 26 CD patients were collected during active disease and during long-term remission (median 4.4 years, interquartile range 3.3-5.1). Plasma protein profiles were generated using quantitative protein mass spectrometry for 159 proteins, including 21 coagulation-related proteins, 18 complement proteins, 15 transport proteins, and 14 apolipoproteins. Protein levels before and after remission were compared with 80 controls (false discovery rate-adjusted t-test) with similar age and sex distribution. RESULTS:During active CD, 78 out of 159 proteins differed from controls, including 11 coagulation proteins, 10 transport proteins, and 3 apolipoproteins. Gelsolin and extracellular matrix protein-1 were most significantly changed. Following remission, 69 proteins changed significantly relative to active disease, but normalization was incomplete. Of the 78 proteins initially altered, 56 were similar to controls upon remission. After remission, 31 proteins remained different from controls, including coagulation proteins factor IX and factor XIII A chain, apolipoprotein A-II, several complement factors and extracellular matrix protein-1. CONCLUSION/CONCLUSIONS:Active CD is associated with profound alterations in plasma protein profiles across various functional domains. Long-term remission is accompanied by substantial, but incomplete normalization of plasma proteins. Sustained plasma protein abnormalities may contribute to persistent morbidities and ongoing adverse health risks after remission of CD.

BACKGROUND:Relacorilant is a selective glucocorticoid receptor modulator designed to reduce excess cortisol activity by competing with cortisol for glucocorticoid receptor binding, mitigating the clinical manifestations of endogenous hypercortisolism (Cushing's syndrome). The aim of this study was to assess the efficacy and safety of relacorilant in adults with endogenous hypercortisolism. METHODS:This multicentre, phase 3, double-blind, placebo-controlled, randomised-withdrawal study enrolled adults with endogenous hypercortisolism and hypertension, hyperglycaemia, or both and was conducted at 77 study centres across 11 countries. Key inclusion criteria included being aged 18-80 years with at least two clinical signs or symptoms of hypercortisolism. In the open-label phase, patients received oral, once-daily relacorilant (escalation from 100 mg up to 400 mg) for 22 weeks. Patients who met response criteria were randomly assigned (1:1) by the interactive web response system to continue relacorilant 400 mg (or highest tolerated dose) or placebo for 12 weeks in the randomised-withdrawal phase. Participants and investigators were masked to treatment assignment. The primary outcome was the proportion of patients who lost hypertension response during the randomised-withdrawal phase compared between relacorilant and placebo at week 12. As per protocol, this outcome was assessed in all participants who received at least one dose of study drug in the study period (intention-to-treat population). Missing randomised-withdrawal week 12 values were considered a loss of response. Safety was assessed in all enrolled patients who received at least one dose of study drug in that period. This study is registered with ClinicalTrials.gov, NCT03697109. FINDINGS/RESULTS:Between Oct 16, 2018, and April 15, 2024, 404 patients were screened, 152 were enrolled, and 95 completed the open-label relacorilant phase. 62 patients met response criteria and were randomly assigned to relacorilant (30 total participants [21 met hypertension response criteria]) or placebo (32 total participants [22 met hypertension response criteria]). In the 30 participants in the relacorilant group, the mean age was 46·6 years (SD 11·0), 22 (73%) were female, and eight (27%) were male. In the 32 participants in the placebo group, the mean age was 48·8 years (SD 14·4), 26 (81%) were female, and six (19%) were male. During the randomised-withdrawal phase, significantly more patients with baseline hypertension who were randomly assigned to placebo lost hypertension control compared with those who continued relacorilant (proportion difference 34%; odds ratio 0·17 [95% CI 0·04-0·77]; p=0·022). In the randomised-withdrawal phase safety population, the most common adverse events in the 30 participants given relacorilant and the 32 participants given placebo were back pain (5 [17%] vs 6 [19%]), acne (3 [10%] vs 0), arthralgia (3 [10%] vs 3 [9%]), bursitis (3 [10%] vs 0), headache (3 [10%] vs 4 [13%]), and insomnia (0 vs 4 [13%]). There were no cases of excessive glucocorticoid receptor antagonism, adrenal insufficiency, vaginal bleeding associated with endometrial hypertrophy, drug-induced hypokalaemia, or drug-induced QT interval prolongation. INTERPRETATION/CONCLUSIONS:Patients treated with relacorilant were more likely to maintain hypertension control compared with patients treated with placebo. The findings support consideration of relacorilant as a therapeutic option to reduce the harmful and debilitating effects of endogenous hypercortisolism. FUNDING/BACKGROUND:Corcept Therapeutics.

BACKGROUND:Treatment for patients with bilateral adrenal tumours and cortisol excess is not standardised and poses a therapeutic dilemma. Untreated cortisol excess is associated with cardiometabolic morbidity and mortality, but bilateral adrenalectomy causes adrenal insufficiency and possibly life-threatening adrenal crises. Data on cardiovascular outcomes by treatment modality are scarce. In this study we aimed to evaluate mid-term and long-term clinical and biochemical outcomes in patients with bilateral adrenal tumours and cortisol excess by treatment strategy and diagnosis. METHODS:This retrospective, international cohort study (in 30 centres across 10 countries in Europe plus Singapore and the USA) included patients with bilateral adrenal tumours of 10 mm or larger, post-dexamethasone serum cortisol concentration of 50 nmol/L or higher, and at least 36 months of follow-up, with data collection beween Feb 2, 2024, and Jan 31, 2025. Patients were excluded if they had adrenocorticotropin hormone (ACTH)-dependent cortisol excess, ACTH-dependent nodular adrenal hyperplasia, partial glucocorticoid resistance syndrome, a diagnosis inconsistent with benign adrenocortical lesions, or received systemic oral or intravenous glucocorticoids other than replacement therapy following adrenalectomy. Primary endpoints were all-cause mortality and clinical and biochemical remission rates. Secondary endpoints were the incidence of cardiovascular events, prevalence of vascular and metabolic comorbidities, and incidence of adrenal crises. FINDINGS/RESULTS:Of 629 patients who were diagnosed between Jan 1, 2000, and Jan 31, 2022, 105 (17%) had Cushing's syndrome and 524 (83%) had mild autonomous cortisol secretion (MACS), median age was 62 years (IQR 54·0-68·0), and 426 (68%) were female. 85 (81%) of 105 patients with Cushing's syndrome underwent surgery, and 384 (73%) of 524 patients with MACS received non-specific symptomatic treatment (ie, never underwent adrenalectomy or received steroidogenesis inhibitors). Over a median follow-up of 6·8 years, biochemical remission was achieved in 46 (45%) of 102 patients with Cushing's syndrome and in 67 (13%) of 517 patients with MACS. In both groups, 7% of patients died (Cushing's syndrome: seven of 105; MACS: 38 of 524) and 12% (13 of 105) of patients with Cushing's syndrome and 16% (82 of 524) of those with MACS had at least one cardiovascular event, without substantial differences across treatments. Smoking emerged as key modifiable mortality and cardiovascular risk factor in all patients, and in patients with MACS who only received non-specific symptomatic therapy, post-dexamethasone cortisol was also associated with increased mortality. Bilateral adrenalectomy led to full biochemical remission, few non-fatal adrenal crises, and improved arterial hypertension. Unilateral adrenalectomy and steroidogenesis inhibitors yielded heterogeneous biochemical outcomes and no substantial comorbidity improvement. Non-specific symptomatic treatment in MACS was associated with worsening of all investigated comorbidities. INTERPRETATION/CONCLUSIONS:Although mortality and cardiovascular event rates were similar across treatments, surgery led to better biochemical control and more favourable comorbidity outcomes. FUNDING/BACKGROUND:None.

PURPOSE/OBJECTIVE:We aimed to determine time trends in incidence, treatment and survival of patients with adrenocortical carcinoma in the Netherlands. METHODS:All 685 adult patients with adrenocortical carcinoma diagnosed between 1993 and 2020 in the Netherlands were included, using the nation-wide prospective Netherlands Cancer Registry. RESULTS:The median age-adjusted incidence rate based on the European Standard Population was 1.62 per million person-years [0.83-2.11] and was stable over time. We saw a gradual increase in stage III on diagnosis (13 to 25%) with a stable proportion of stage IV (40%). The five-year survival remained stable over time for stage I-II at 65% and stage III at 35%, while the survival for stage IV increased from 3% in 1993-1996 to 11% in 2017-2020. Since the Dutch Adrenal Network was founded in 2004, more patients were referred to an expert center (p<0.001), which was associated with increased survival (adjusted HR 0.70, 95%CI[0.57-0.85]). Multivariate cox-regression showed increased survival in all stages when treated with adrenalectomy (adjusted HR 0.53, 95%CI[0.43-0.65]) and mitotane therapy (adjusted HR 0.73, 95%CI[0.55-0.98]). In stage IV disease, adrenalectomy, surgical control of disease, chemotherapy and mitotane therapy were associated with increased survival. However, only 58% of mitotane users reached a therapeutic drug level and 59.5% discontinued treatment prematurely. CONCLUSIONS:The incidence of adrenocortical carcinoma is stable over time. The five-year survival for stage I-III remained stable, while the survival for stage IV increased. Factors associated with increased survival are centralization of care, adrenalectomy, surgical control of disease, chemotherapy and mitotane therapy.

Cushing's disease (CD) is an endogenous hypercortisolism state caused by an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. Medical therapy is an important second-line treatment for CD. New pharmacologic agents for the treatment of patients with CD are under development. New possible intervention targets include various receptors and pathways in the corticotroph tumor, the hormone ACTH, and its receptor and enzymes involved in cortisone metabolism. This part of the article will focus on tailoring pharmacologic therapy according to patient specific characteristics, long-term medical therapy and development of new drugs for CD.

Cushing's disease (CD) is an endogenous hypercortisolism state caused by an adrenocorticotropic hormone secreting pituitary adenoma. CD is associated with vast comorbidities and has a significant detrimental effect on quality of life as well as longevity. First line treatment for CD is transsphenoidal surgery (TSS) while medical therapy is an important second line treatment in cases of TSS failure or infeasibility. Current existing medications for CD target different processes related to CD including the corticotroph adenoma, cortisol adrenal manufacturing mechanisms, and glucocorticoid receptor blockage and widely differ in advantages as well as adverse effects. In depth acquaintance with the specific characteristics of each drug is needed in order to provide patients with the appropriate therapy according to their specific needs.

BACKGROUND:Cyclic Cushing's syndrome (cCS) features fluctuating cortisol secretion, often causing diagnostic errors or delays, and possibly poorer outcomes. We aimed to identify unpublished cCS cases to characterise clinical challenges and guide strategies for improving outcomes by characterising cycle patterns, peak frequency, and evaluating complications. METHODS:This was a retrospective observational study at 43 endocrine centres in 21 countries, including patients with confirmed Cushing's syndrome showing two or more hypercortisolaemic peaks and one or more spontaneous eucortisolaemic or hypocortisolaemic trough. Data included both clinical (eg, comorbidities and physical signs of cortisol excess) and biochemical (eg, screening and confirmatory tests) parameters, imaging, treatment, complications, and outcomes. FINDINGS/RESULTS:Between Dec 1, 2023 and Feb 2, 2025, 116 potentially eligible patients were identified and 110 were included. Most patients were female (84 [76%] of 110 patients), with a median age at diagnosis of 44·0 years (IQR 31·8-58·3). cCS origin was pituitary in 70 (64%), ectopic in 25 (23%), adrenal in three (3%), and occult in 12 (11%). Cyclicity was primarily determined by 24 h urinary free cortisol, with median peaks of 7·40 × ULN (range 0·44-299) and troughs of 0·31 × ULN (0·02-0·98). The median peak count was 3·0 (IQR 2·0-4·0), mostly (55 [86%] of 64 patients) occurring at irregular intervals, and was most frequent and pronounced in ectopic cCS. Symptoms worsened in 87 (81%) of 108 patients during peaks and improved in 79 (74%) of 107 patients during troughs; 31 (28%) of 110 patients had spontaneous adrenal insufficiency. Bilateral inferior petrosal sinus sampling (BIPSS) was performed during troughs in 14 patients (18% of the 78 procedures done). Imaging missed tumours in 35 (32%) of the 110 patients, and nine (8%) underwent unwarranted surgeries at the wrong anatomical site due to misclassification. After 5·8 years (IQR 2·6-10·5) median follow-up, 55 (50%) of 110 patients had complete biochemical surgical remission, seven (6%) had spontaneous remission, 22 (20%) were medically controlled, six (5%) had partial remission, 11 (10%) remained uncontrolled, nine (8%) were lost to follow-up. During the entire observation period, 3% (3/110) died. Delayed diagnosis (45 [41%] of 110 patients) and therapy (47 [43%]) were also observed. INTERPRETATION/CONCLUSIONS:Even in specialised centres, cCS diagnosis and management remain challenging with high rates of spontaneous adrenal insufficiency, inappropriate surgeries, and poor outcomes. Ectopic cCS showed the most frequent and severe peaks. These findings might help to guide imaging localisations or the timing of BIPSS in patients with active occult ACTH-dependent cCS. Hypercortisolism needs to be biochemically confirmed before BIPSS to enable correct tumour localisation. Patients with suspected or proven cCS should be equipped with salivary cortisol collection kits to capture dynamic changes as well as being prescribed glucocorticoids to be used as a precaution. FUNDING/BACKGROUND:None.

CONTEXT/BACKGROUND:The biochemical diagnosis of carcinoid syndrome (CS) is established through the measurement of 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA), but these measurements are prone to sampling error and may be troublesome for patients. Serum 5-HIAA measurements might constitute a more reliable and convenient alternative to diagnose CS. OBJECTIVE:To assess the diagnostic value of serum 5-HIAA measurements in patients with CS. DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Tertiary care hospital. PATIENTS/METHODS:379 patients with a neuroendocrine tumor (NET), of whom 136 (35.9%) had CS, and 153 control samples were included. INTERVENTION/METHODS:Paired serum and 24-hour urine 5-HIAA measurements. MAIN OUTCOME MEASURE(S)/METHODS:Performances of serum and 24-hour urine 5-HIAA for the diagnosis of CS, measured by area under the receiver operating characteristics curve (AUROC). RESULTS:Serum 5-HIAA performance was similar to that of 24-hour urine 5-HIAA for the diagnosis of CS in the total NET cohort (n=379, AUROC 0.824 vs. 0.843, p=0.50) and in a subgroup of somatostatin analogue (SSA)-naïve patients (n=141, AUROC 0.915 vs. 0.938, p=0.66). Optimal cutoff value of serum 5-HIAA for the diagnosis of CS was 139.4 nmol/L (sensitivity 96.3%, specificity 87.6%) as determined in a subgroup analysis of SSA-naive patients with CS and controls. Serum 5-HIAA correlated well with 24-hour urine 5-HIAA (r=0.892, p<0.001) and the presence of flushing, diarrhea and carcinoid heart disease (OR 1.047-1.073 for every 100 nmol/L increase, p<0.001). CONCLUSIONS:Serum 5-HIAA measurements are equivalent to 24-hour urine 5-HIAA measurements for the diagnosis of CS in patients with NET and form an accessible alternative.

The majority of prolactinomas are treated with dopamine agonists (DA) with excellent response, however DA-resistance occurs in 10% of prolactinomas. Somatostatin (SST) receptors have been increasingly studied in prolactinomas. There are five SST receptor subtypes and a significant number of prolactinomas show expression of SST₅ and SST₁ mRNA. The somatostatin analog (SSA) pasireotide, which has 40-fold greater binding affinity to SST₅ compared to first-generation SSAs, shows promising results in case reports of DA-resistant prolactinomas. This two-center retrospective cohort study investigated the expression patterns of dopamine 2 (D2R), SST₂ and SST₅ receptors in surgical specimen of 34 patients with prolactinomas, 22 of which were DA-resistant. In vitro effects of cabergoline, octreotide and pasireotide on prolactin production was also examined in cultured prolactinoma cells. Receptor expression was scored using the immunoreactivity score (IRS). 31/34(91%) patients used DA preoperatively; 22/34(64.7%) were DA-resistant. Receptor expression in the cases was 97.1% for D2R, 70.6% for SST₅ and 41.2% for SST₂. In the majority of SST₂ positive cases SST₂ expression was very low. In in vitro studies comparing the effects of octreotide, pasireotide, and cabergoline on prolactin secretion, octreotide was the least potent drug and cabergoline was the most potent. SST₅ and D2R expression was highest in prolactinomas showing the highest response to pasireotide and cabergoline in vitro (median D2R IRS 1.0 vs 8.0 for < 50% vs. > 50% inhibition by cabergoline and median SST₅ IRS 3.5 avs. 12.0 for < 50% vs. > 50% inhibition by pasireotide). In a subgroup, pasireotide inhibited prolactin secretion with comparable potency to cabergoline. Targeting SST₅ with pasireotide may be a potential treatment modality for further clinical investigation in the treatment of a subset of DA resistant or intolerant prolactinomas.

First-line treatment of endogenous Cushing's syndrome (CS) is surgical removal of the tumor responsible for cortisol excess. However, medical therapy has an established role in treatment when patients are not surgical candidates or decline surgery, residual or recurrent disease is present and not amenable to repeat resection, and control of hypercortisolism is needed either preoperatively or while awaiting the effects of radiotherapy. The approach to medical therapy should be tailored based on the etiology, degree of hypercortisolism, and patient characteristics. Currently available medical therapy for all etiologies of CS either blocks adrenal production of cortisol or blocks its action at the level of the glucocorticoid receptor. Currently available medical therapy for Cushing's disease (CD) targets the adrenocorticotropic hormone-secreting pituitary tumor through activation of somatostatin and dopamine receptors, alkylating DNA damage, or immune system activation. More focused therapy with greater efficacy and fewer adverse effects is needed, particularly in the case of CD, with potential targets and drugs identified and in development.